Abstract
It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4h/h) or human CD34+ stem cell-reconstituted NSG™ mice. In Ctla4h/m mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody L3D10 is comparable to the non-blocking Ipilimumab in causing tumor rejection. Remarkably, L3D10 progenies that lose blocking activity during humanization remain fully competent in inducing Treg depletion and tumor rejection. Anti-B7 antibodies that effectively block CD4 T cell activation and de novo CD8 T cell priming in lymphoid organs do not negatively affect the immunotherapeutic effect of Ipilimumab. Thus, clinically effective anti-CTLA-4 mAb causes tumor rejection by mechanisms that are independent of checkpoint blockade but dependent on the host Fc receptor. Our data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis and provide new insights for the next generation of safe and effective anti-CTLA-4 mAbs.
Highlights
The classic checkpoint blockade hypothesis states that cancer immunity is restrained by two distinct checkpoints: the first is the CTLA-4:B7 interaction that limits priming of naive T cells in lymphoid organs, while the second is the PD-1/B7-H1(PD-L1)interaction that results in exhaustion of effector T cells within the tumor microenvironment.[1]
We tested the therapeutic response of the two anti-CTLA-4 monoclonal antibodies (mAbs) in the Ctla4h/m mice in which the anti-human CTLA-4 mAbs can bind to a maximum of 50% of CTLA-4 molecules and in which neither antibody can block the B7-CTLA-4 interaction to achieve upregulation of B7 on dendritic cells (DCs) (Fig. 5f)
Since anti-B7 mAbs did not interfere with immunotherapeutic effect of Ipilimumab (Fig. 9), the findings presented in Fig. 10 suggest that de novo T cell priming after Ipilimumab treatment is not required for achieving the immunotherapeutic effects of Ipilimumab
Summary
The classic checkpoint blockade hypothesis states that cancer immunity is restrained by two distinct checkpoints: the first is the CTLA-4:B7 interaction that limits priming of naive T cells in lymphoid organs, while the second is the PD-1/B7-H1(PD-L1). Interaction that results in exhaustion of effector T cells within the tumor microenvironment.[1] Since several new targets have been under evaluation in clinical trials[2] and multiple mechanisms have been described for the targeting reagents.[3] Anti-CTLA-4 monoclonal antibodies (mAbs) induce cancer rejection in mice[4,5,6] and patients.[7,8] Recently, a number of additional mechanisms were proposed to explain the immunotherapeutic effect of anti-. We used human CTLA4 gene knock-in mice as well as mice reconstituted with human hematopoietic stem cells to systematically evaluate whether blocking the B7-CTLA-4 interaction under physiologically relevant conditions is required for the immunotherapeutic effect of anti-human CTLA-4 mAbs. Our data suggest that blocking the B7-CTLA-4 interaction may not contribute to the cancer immunotherapeutic effect.
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